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Type: Journal article
Title: Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes
Author: Chong, C.-.E.
Venugopal, P.
Stokes, P.
Lee, Y.
Brautigan, P.
Yeung, D.
Babic, M.
Engler, G.
Lane, S.
Klingler-Hoffmann, M.
Matthews, J.
D'Andrea, R.
Brown, A.
Hahn, C.
Scott, H.
Citation: Leukemia, 2018; 32(1):194-202
Publisher: Springer Nature
Issue Date: 2018
ISSN: 0887-6924
Statement of
C-E Chong, P Venugopal, PH Stokes, YK Lee, PJ Brautigan, DTO Yeung, M Babic, GA Engler, SW Lane, M Klingler-Hoffmann, JM Matthews, RJ D'Andrea, AL Brown, CN Hahn, and HS Scott
Abstract: Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.
Keywords: COS Cells; Hematopoietic System; Animals; Mice, Inbred C57BL; Humans; Mice; Genetic Predisposition to Disease; Cell Differentiation; Transcription, Genetic; Genotype; Phenotype; Mutation; Female; Male; GATA2 Transcription Factor; HEK293 Cells; Haploinsufficiency; Chlorocebus aethiops
Rights: © The Author(s) 2018 This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://
RMID: 0030073168
DOI: 10.1038/leu.2017.196
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